Certain imidazoquinoxalines: a new class of GABA brain receptor ligands

ABSTRACT

This invention encompasses compounds of the formula:                    
     and the pharmaceutically acceptable non-toxic salts thereof wherein R 1 , R 2 , R 3 , R 4 , X, and W are variables. These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs thereof and are useful in the diagnosis and treatment of anxiety, sleep, and seizure disorders, overdose with benzodiazepine drugs, and enhancement of memory.

This application is a continuation of U.S. application Ser. No.09/067,112, filed Apr. 27, 1998, ABN which is a Continuation of U.S.application Ser. No. 08/440,696, filed May 15, 1995, now U.S. Pat. No.5,744,602, which is a which is a Continuation of U.S. application Ser.No. 08/050,068, filed Apr. 29, 1993, now abandoned, which is a NationalPhase filed under 35 U.S.C. 371 of International ApplicationPCT/US91/07881, filed Oct. 31, 1991, now abandoned, which is a CIP ofSer. No. 07/606,769, filed Oct. 31, 1990, now U.S. Pat. No. 5,130,430.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain imidazoquinoxalines which selectivelybind to GABAa receptors. This invention also relates to pharmaceuticalcompositions comprising such compounds. It further relates to the use ofsuch compounds in treating anxiety, sleep and seizure disorders, andoverdoses of benzodiazepine-type drugs, and enhancing alertness. Theinteraction of imidazoquinoxalines of the invention with a GABA bindingsite, the benzodiazepines (BDZ) receptor, is described. This interactionresults in the pharmacological activities of these compounds.

2. Description of the Related Art

γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitoryamino acid transmitters in the mammalian brain. Over 30 years haveelapsed since its presence in the brain was demonstrated (Roberts &Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187:65-69, 1950). Since that time, an enormous amount of effort has beendevoted to implicating GABA in the etiology of seizure disorders, sleep,anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8:21-44, 1985). Widely, although unequally, distributed through themammalian brain, GABA is said to be a transmitter at approximately 30%of the synapses in the brain. In most regions of the brain, GABA isassociated with local inhibitory neurons and only in two regions is GABAassociated with longer projections. GABA mediates many of its actionsthrough a complex of proteins localized both on cell bodies and nerveendings; these are called GABAa receptors. Postsynaptic responses toGABA are mediated through alterations in chloride conductance thatgenerally, although not invariably, lead to hyperpolarization of thecell. Recent investigations have indicated that the complex of proteinsassociated with postsynaptic GABA responses is a major site of actionfor a number of structurally unrelated compounds capable of modifyingpostsynaptic responses to GABA. Depending on the mode of interaction,these compounds are capable of producing a spectrum of activities(either sedative, anxiolytic, and anticonvulsant, or wakefulness,seizures, and anxiety).

1,4-Benzodiazepines continue to be among the most widely used drugs inthe world. Principal among the benzodiazepines marketed arechlordiazepoxide, diazepam, flurazepam, and triazolam. These compoundsare widely used as anxiolytics, sedative-hypnotics, muscle relaxants,and anticonvulsants. A number of these compounds are extremely potentdrugs, such potency indicates a site of action with a high affinity andspecificity for individual receptors. Early electrophysiological studiesindicated that a major action of benzodiazepines was enhancement ofGABAergic inhibition. The benzodiazepines were capable of enhancingpresynaptic inhibition of a monosynaptic ventral root reflex, aGABA-mediated event (Schmidt et al., 1967, Arch. Exp. Path. Pharmakol.258: 69-82). All subsequent electrophysiological studies (reviewed inTallman et al. 1980, Science 207:274-81, Haefley et al., 1981, Handb.Exptl. Pharmacol. 33: 95-102) have generally confirmed this finding, andby the mid-1970s, there was a general consensus amongelectrophysiologists that the benzodiazepines could enhance the actionsof GABA.

With the discovery of the “receptor” for the benzodiazepines and thesubsequent definition of the nature of the interaction between GABA andthe benzodiazepines, it appears that the behaviorally importantinteractions of the benzodiazepines with different neurotransmittersystems are due in a large part to the enhanced ability of GABA itselfto modify these systems. Each modified system, in turn, may beassociated with the expression of a behavior.

Studies on the mechanistic nature of these interactions depended on thedemonstration of a high-affinity benzodiazepine binding site (receptor).Such a receptor is present in the CNS of all vertebratesphylogenetically newer than the boney fishes (Squires & Braestrup 1977,Nature 166: 732-34, Mohler & Okada, 1977, Science 198: 854-51, Mohler &Okada, 1977, Br. J. Psychiatry 133: 261-68). By using tritiateddiazepam, and a variety of other compounds, it has been demonstratedthat these benzodiazepine binding sites fulfill many of the criteria ofpharmacological receptors; binding to these sites in vitro is rapid,reversible, stereospecific, and saturable. More importantly, highlysignificant correlations have been shown between the ability ofbenzodiazepines to displace diazepam from its binding site and activityin a number of animal behavioral tests predictive of benzodiazepinepotency (Braestrup & Squires 1978, Br. J. Psychiatry 133: 249-60, Mohler& Okada, 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J.Psychiatry 133: 261-68). The average therapeutic doses of these drugs inman also correlate with receptor potency (Tallman et al. 1980, Science207: 274-281).

In 1978, it became clear that GABA and related analogs could interact atthe low affinity (1 mM) GABA binding site to enhance the binding ofbenzodiazepines to the clonazepan-sensitive site (Tallman et al. 1978,Nature, 274: 383-85). This enhancement was caused by an increase in theaffinity of the benzodiazepine binding site due to occupancy of the GABAsite. The data were interpreted to mean that both GABA andbenzodiazepine sites were allosterically linked in the membrane as partof a complex of proteins. For a number of GABA analogs, the ability toenhance diazepam binding by 50% of maximum and the ability to inhibitthe binding of GABA to brain membranes by 50% could be directlycorrelated. Enhancement of benzodiazepine binding by GABA agonists isblocked by the GABA receptor antagonist(+) bicuculline; the stereoisomer(−) bicuculline is much less active (Tallman et al., 1978, Nature, 274:383-85).

Soon after the discovery of high affinity binding sites for thebenzodiazepines, it was discovered that a triazolopyridazine couldinteract with benzodiazepine receptors in a number of regions of thebrain in a manner consistent with receptor heterogeneity or negativecooperativity. In these studies, Hill coefficients significantly lessthan one were observed in a number of brain regions, including cortex,hippocampus, and striatum. In cerebellum, triazolopyridazine interactedwith benzodiazepine sites with a Hill coefficient of 1 (Squires et al.,1979, Pharma. Biochem. Behav. 10: 825-30, Klepner et al. 1979,Pharmacol. Biochem. Behav. 11: 457-62). Thus, multiple benzodiazepinereceptors were predicted in the cortex, hippocampus, striatum, but notin the cerebellum.

Based on these studies, extensive receptor autoradiographic localizationstudies were carried out at a light microscopic level. Although receptorheterogeneity has been demonstrated (Young & Kuhar 1980, J. Pharmacol.Exp. Ther. 212: 337-46, Young et al., 1981 J. Pharmacol Exp. ther 216:425-430, Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 670-75), nosimple correlation between localization of receptor subtypes and thebehaviors associated with the region has emerged from the early studies.In addition, in the cerebellum, where one receptor was predicted frombinding studies, autoradiography revealed heterogeneity of receptors(Niehoff et al., 1982, Pharmacol. Exp. Ther. 221: 670-75).

A physical basis for the differences in drug specificity for the twoapparent subtypes of benzodiazepine sites has been demonstrated bySieghart & Karobath, 1980, Nature 286: 285-87. Using gel electrophoresisin the presence of sodium dodecyl sulfate, the presence of severalmolecular weight receptors for the benzodiazepines has been reported.The receptors were identified by the covalent incorporation ofradioactive flunitrazepam, a benzodiazepine which can covalently labelall receptor types. The major labeled bands have moelcular weights of50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines inhibitlabeling of the slightly higher molecular weight forms (53,000, 55,000,57,000) (Seighart et al. 1983, Eur. J. Pharmacol. 88: 291-99).

At that time, the possibility was raised that the multiple forms of thereceptor represent “isoreceptors” or multiple allelic forms of thereceptor (Tallman & Gallager 1985, Ann. Rev. Neurosci. 8: 21-44).Although common for enzymes, genetically distinct forms of receptorshave not generally been described. As we begin to study receptors usingspecific radioactive probes and electrophoretic techniques, it is almostcertain that isoreceptors will emerge as important in investigations ofthe etiology of psychiatric disorders in people.

The GABAa receptor subunits have been cloned from bovine and human cDNAlibraries (Schoenfield et al., 1988; Duman et al., 1989). A number ofdistinct cDNAs were identified as subunits of the GABAa receptor complexby cloning and expression. These are categorized into α, β, γ, δ, ε, andprovide a molecular basis for the GABAa receptor heterogeneity anddistinctive regional pharmacology (Shivvers et al., 1980; Levitan etal., 1989). The γ subunit appears to enable drugs like benzodiazepinesto modify the GABA responses (Pritchett et al., 1989). The presence oflow Hill coefficients in the binding of ligands to the GABAa receptorindicates unique profiles of subtype specific pharmacological action.

Drugs that interact at the GABAs receptor can possess a spectrum ofpharmacological activities depending on their abilities to modify theactions of GABA. For example, the beta-carbolines were first isolatedbased upon their ability to inhibit competitively the binding ofdiazepam to its binding site (Nielsen et al., 1979, Life Sci. 25:679-86). The receptor binding assay is not totally predictive about thebiological activity of such compounds; agonists, partial agonists,inverse agonists, and antagonists can inhibit binding. When thebeta-carboline structure was determined, it was possible to synthesize anumber of analogs and test these compounds behaviorally. It wasimmediately realized that the beta-carbolines could antagonize theactions of diazepam behaviorally (Tenen & Hirsch, 1980, Nature 288:609-10). In addition to this antagonism, beta-carbolines possessintrinsic activity of their own opposite to that of the benzodiazepines;they become known as inverse agonists.

In addition, a number of other specific antagonists of thebenzodiazepine receptor were developed based on their ability to inhibitthe binding of benzodiazepines. The best studied of these compounds isan imidazodiazepine. (Hunkeler et al., 1981, Nature 290: 514-516). Thiscompound is a high affinity competitive inhibitor of benzodiazepine andbeta-carboline binding and is capable of blocking the pharmacologicalactions of both these classes of compounds. By itself, it possesseslittle intrinsic pharmacological activity in animals and humans(Hunkeler et al., 1981, Nature 290: 514-16; Darragh et al., 1983, Eur.J. Clin. Pharmacol. 14: 569-70). When a radiolabeled form of thiscompound was studied (Mohler & Richards, 1981, Nature 294: 763-65). itwas demonstrated that this compound would interact with the same numberof sites as the benzodiazepines and beta-carbolines, and that theinteractions of these compounds were purely competitive. This compoundis the ligand of choice for binding to GABAa receptors because it doesnot possess receptor subtype specificity and measures each state of thereceptor.

The study of the interactions of a wide variety of compounds similar tothe above has led to the categorizing of these compounds. Presently,those compounds possessing activity similar to the benzodiazepines arecalled agonists. Compounds possessing activity opposite tobenzodiazepines are called inverse agonists, and the compounds blockingboth types of activity have been termed antagonists. This categorizationhas been developed to emphasize the fact that a wide variety ofcompounds can produce a spectrum of pharmacological effects, to indicatethat compounds can interact at the same receptor to produce oppositeeffects, and to indicate that beta-carbolines and antagonists withintrinsic anxiogenic effects are not synonymous. A biochemical test forthe pharmacological and behavioral properties of compounds that interactwith the benzodiazepine receptor continues to emphasize the interactionwith the GABAergic system. In contrast to the benzodiazepines, whichshow an increase in their affinity due to GABA (Tallman et al., 1978,Nature 274: 383-85, Tallman et al., 1980, Science 207: 274-81),compounds with antagonist properties show little GABA shift (i.e.,change in receptor affinity due to GABA) (Mohler & Richards 1981, Nature294: 763-65), and the inverse agonists actually show a decrease inaffinity due to GABA (Braestrup & Nielson 1981, Nature 294: 472-474).Thus, the GABA shift predicts generally the expected behavioralproperties of the compounds.

Various compounds have been prepared as benzodiazepine agonists andantagonists. For example, U.S. Pat. Nos. 4,312,870 and 4,713,383, andEuropean Patent Application EP 181,282 disclose assorted compoundsuseful in treating anxiety or depression. U.S. Pat. No. 4,713,383teaches compounds of the formula:

wherein R₁=(un)substituted Ph, (dihydro)furanyl, tetrahydrofuranyl,(dihydro)thienyl, tetrahydrothienyl, pyranyl, ribofuranosyl, allC-attached; R₂=H, alkyl; X=O, S, R₃N; R₃=H, alkenyl, alkynyl, C₃₋₂₀cycloalkyl, (un)substituted alkyl, aryl, aralkyl, where aryl is Ph,pyridinyl, thienyl, furanyl; ring A may be substituted by alkyl, alkoxy,halo, amino, alkylthio, etc.

European Patent Application EP 181,282 discloses compounds of theformula:

wherein R₁=(substituted) Ph or heterocycle; R₂=H, alkyl, alkenyl,hydroxyalkyl, aralkyl, aralkenyl, aryl; R₃=H, alkyl, alkoxy, HO, halo,F₃C, O₃N, H₂N, alkylthio, alkylsulfinyl, alkylsulfonyl, aralkoxy; X=O,S, NR₄; and R₄=H, alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl, aryl,(substituted) aminoaklyl, hydroxyalkyl.

U.S. Pat. No. 4,312,870 teaches compounds of formulas:

where

Ph is 1,2-phenylene, unsubstituted or substituted by up to 3 identicalor different members selected from lower alkyk, lower alkoxy, loweralkylthio, hydroxy, halogeno, trifluoromethyl, nitro, amino, mono- ordi-lower alkylamino, cyano, carbamoyl and carboxy; R is unsubstituted orsubstituted phenyl as defined by H—Ph, pyridyl, lower alkylpyridyl, orhalogenopyridyl; R¹ is hydrogen, lower alkyl or lower (hydroxy,dialkylamino or H—Ph)-alkyl; and R₂ is hydrogen or lower alkyl alkyl;their 3-hydroxy-tautomers; lower alkanoyl, carbamoyl, mono- or di-loweralkyl-carbamoyl derivatives of said (hydroxy or amino)-(phenyl orphenylene) compounds; and

where

R″ is hydrogen, alkyl or alkoxy with up to 4 carbon atoms each, hydroxy,fluoro, chloro, bromo, or trifluoromethyl, and R′ is hydrogen, o- orm-fluoro-, or it is p-fluoro when R″ is chloro.

The compounds of the present invention differ from these compounds.These compounds are not imidazoquinoxalines and lack the various ringsubstituents of the compounds of the present invention.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact witha GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in enhancingalertness, treatment of seizure, anxiety, and sleep disorders, andtreatment of benzodiazepine overdoses. Accordingly, a broad embodimentof the invention is directed to compounds of Formula I:

and the pharmaceutically acceptable non-toxic salts thereof

wherein:

R₁ and R₄ are the same or different and represent

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

X is

hydrogen, halogen, hydroxy, or amino; or

mono- or dialkylamino where each alkyl is lower alkyl having 1-6 carbonatoms;

W is

phenyl, thienyl, or pyridyl, or

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

R₂ and R₃ are the same or different and represent

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thio)chromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thio)chromanyl, 1-(1,2,3,4-tetrahydronaphthyl), each ofwhich is monosubstituted with halogen, straight or branched chain loweralkyl having 1-6, carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

—CONR₆R₇ or —(CH₂)_(n)NR₆R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms:

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl piperazyl;

—NR₈CO₂R₉ where R₈ and R₉ are the same or different and representhydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms; or

C(OH)R₁₀R₁₁ where R₁₀ and R₁₁ are the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms.

These compounds are highly selective agonists, antagonists or inverseagonists for GABAa brain receptors or prodrugs of agonists, antagonistsor inverse agonists for GABAa brain receptors. These compounds areuseful in the diagnosis and treatment of anxiety, sleep, and seizuredisorders, overdose with benzodiazepine drugs, and enhancement ofmemory.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1A-E show representative imidazoquinoxalines of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by the following general formula I:

and pharmaceutically acceptable non-toxic salts thereof

wherein:

R₁ and R₄ are the same or different and represent

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

X is

hydrogen, halogen, hydroxy, or amino; or

mono- or dialkylamino where each alkyl is lower alkyl having 1-6 carbonatoms;

W is

phenyl, thienyl, or pyridyl, or

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

R₂ and R₃ are the same or different and represent

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thio)chromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thio)chromanyl, 1-(1,2,3,4-tetrahydronaphthyl), each ofwhich is monosubstituted with halogen, straight or branched chain loweralkyl having 1-6, carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

—CONR₆R₇ or —(CH₂)_(n)NR₆R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms;

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆R₇ is a heterocyclic group which is morpholyl, piperidyl, pyrrolidyl,or N-alkyl piperazinyl;

—NR₈CO₂R₉ where R₈ and R₉ are the same or different and representhydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms; or

C(OH)R₁₀ R₁₁ where R₁₀ and R₁₁ arm the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms.

In addition, the present invention encompasses compounds of Formula II.

where:

R₁ and R₄ are the same or different and represent

hydrogen, halogen or straight or branched chain lower alkyl having 1-6carbon atoms;

X is

hydrogen, halogen, hydroxy, or amino; or

mono- or dialkylamino where each alkyl is straight or branched chainlower alkyl having 1-6 carbon atoms;

W is

phenyl or a phenyl group mono or disubstituted with halogen, hydroxy,amino, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms.

The present invention also encompases compounds of Formula III:

where:

W is

phenyl or a phenyl group mono or disubstituted with halogen, hydroxy,amino, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms.

The present invention also encompases compounds of Formula IV:

where:

W is

phenyl or a phenyl group mono or disubstituted with halogen, hydroxy,amino, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; and

R₂ and R₃ are the same or different and represent

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thio)chromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thio)chromanyl, 1-(1,2,3,4-tetrahydronaphthyl), each ofwhich is monosubstituted with halogen, straight or branched chain loweralkyl having 1-6, carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

CONR₆R₇ or —(CH₂)_(n)NR₆R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms;

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆R₇ is a heterocyclic group which is morpholyl, piperidyl, pyrrolidyl,or N-alkyl piperazinyl;

—NR₈CO₂R₉ where R₈ and R₉ are the same or different and representhydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms; or

C(OH)R₁₀ R₁₁ where R₁₀ and R₁₁ are the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluene sulfonic, hydroiodic, acetic and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Figure Iand their pharmaceutically acceptable salts. The present invention alsoencompasses the acylated prodrugs of the compounds of Formula I. Thoseskilled in the an will recognizwe various synthetic methodologies whichmay be employed to prepare non-toxic pharmaceutically acceptableaddition salts and acylated prodrugs of the compounds encompassed byFormula I.

By lower alkyl in the present invention is meant straight or branchedchain alkyl groups having 1-6 carbon atoms, such as, for example,methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl.

By lower alkoxy in the present invention is meant straight or branchedchain alkoxy groups having 1-6 carbon atoms, such as, for example,methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,and 3-methylpentoxy.

By halogen in the present invention is meant fluorine, bromine,chlorine, and iodine.

By N-alkylpiperazinyl in the invention is meant radicals of the formula:

where R is a straight or branched chain lower alkyl as defined above.

By 4-(thio)chromanyl is meant a radical of the formula:

The pharmaceutical utility of compounds of this invention art indicatedby the following assay for GABAa receptor activity.

Assays are carried out as described in Thomas and Tallman (J. Bio. Chem.156: 9838-9842, J. Neurosci. 3:433-440, 1983). Rat cortical tissue isdissected and homogenized in 25 volumes (w/v) of 0.05 M Tris HCl buffer(pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4°)at 20,000×g for 20′. The supernatant is decanted and the pellet isrehomogenized in the same volume of buffer and again centrifuged at20,000×g. The supernatant is decanted and the pellet is frozen at −20°C. overnight. The pellet is then thawed and rehomogenized in 25 volume(original wt/vol) of buffer and the procedure is carried out twice. Thepellet is finally resuspended in 50 volumes (w/vol of 0.05 M Tris HClbuffer (pH 7.4 at 40° C.).

Incubations contain 100 μl of tissue homogenate, 100 μl of radioligand0.5 nM (³H-RO15-1788 [³H-Flumazenil] specific activity 80 Ci/mmol). drugor blocker and buffer to a total volume of 500 μl. Incubations arecarried for 30 min at 4° C. then are rapidly filtered through GFBfilters to separate free and bound ligand. Filters are washed twice withfresh 0.05 M Tris HCl buffer (pH 7.4 at 4° C.) and counted in a liquidscintillation counter. 1.0 mM diazepam is added to some tubes todetermine nonspecific binding. Data are collected in triplicatedeterminations, averaged and % inhibition of total specific binding iscalculated. Total Specific Binding=Total−Nonspecific. In some cases, theamounts of unlabeled drugs is varied and total displacement curves ofbinding are carried out. Data are converted to a form for thecalculation of IC₅₀ and Hill Coefficient (nH). Data for the compounds ofthis invention are listed in Table I.

TABLE I Compound Number¹ IC₅₀(μM) 1 0.0095 3 0.015 4 0.0095 5 0.016 330.0024 ¹Compound numbers relate to compouuds shown in FIG. 1.

Compounds 1, 3 and 4 are particularly preferred embodiments of thepresent invention.

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

An illustration of the preparation of compounds of the present inventionis given in Scheme I and Scheme II. Those having skill in the an willrecognize that the starting materials may be varied and additional stepsemployed to produce compounds encompassed by the present invention, asdemonstrated by the following examples.

where:

R₁ and R₄ are the same or different and represent

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

X is

hydrogen, halogen, hydroxy, or amino; or

mono- or dialkylamino where each alkyl is lower alkyl having 1-6 carbonatoms;

W is

phenyl, thienyl, or pyridyl, or

phenyl, thienyl, or pyridyl, each of which may be mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, amino, mono or dialkylamino where each alkyl is straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;

R₂ and R₃ are the same or different and represent

hydrogen, halogen, hydroxy, amino, 1-indanyl, 4-(thio)chromanyl,1-(1,2,3,4-tetrahydronaphthyl);

1-indanyl, 4-(thio)chromanyl, 1-(1,2,3,4-tetrahydronaphthyl), each ofwhich is monosubstituted with halogen, straight or branched chain loweralkyl having 1-6, carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms;

OR₅, COR₅, CO₂R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl, pyridyl,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

—CONR₆R₇ or —(CH₂)_(n)NR₆R₇ where

n is 0, 1, or 2;

R₆ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms;

R₇ is hydrogen, phenyl, pyridyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkylis straight or branched chain lower alkyl having 1-6 carbon atoms; or

NR₆R₇ forms a heterocyclic group which is morpholyl, piperidyl,pyrrolidyl, or N-alkyl;

—NR₈CO₂R₉ where R₈ and R₉ are the same or different and representhydrogen, phenyl, pyridyl, straight or branched chain lower alkyl having1-6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms; or

C(OH)R₁₀ R₁₁ where R₁₀ and R₁₁ are the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms.

In some cases protection of certain reactive functionalities may benecessary to achieve some of the above transformations. In general theneed for such protecting groups will be obvious to those skilled in theart of organic synthesis as well as the conditions necessary to attachand remove such groups.

EXAMPLE I

To a solution of 2-Nitrophenyl isocyanate (3.34 g) in 100 mL of toluenewas added aniline (2 g). The mixture was stirred at 20° C. for 30 min.Hexane (300 mL) was added and the resulting solid was filtered and driedto yield N-(2-Nitrophenyl)-N′-phenyl-urea as a light yellow solid.

EXAMPLE II

To a solution of Diethyl nitroterephthalate (17.9 g) in 300 mL ethanolwas added 1N NaOH (70 mL) and stirred overnight. 1N HCl (70 mL) wasadded and the reaction was partitioned between methylene chloride (200mL) and water (200 mL). The aqueous layer was extracted an additionalthree times. The combined organic extracts were dried and the solventremoved in vacuo to afford Ethyl-3-nitro-4-carboxybenzoate as a whitesolid.

EXAMPLE III

To Diphenylphosphoryl azide (5.75 g) in anhydrous toluene (50 mL) al.100° C. under nitrogen was added dropwise a solution containingEthyl-3-nitro-4-carboxybenzoate (5 g) and triethylamine (4 mL) inanhydrous toluene (50 mL). The mixture was stirred for 1 h followed bythe addition of aniline (5 mL). and the reaction was allowed to cool toroom temperature (40 min). Ethyl acetate (300 mL) was added and thesolution was washed successively with 1N HCl (300 mL), water (300 mL),1N NaOH (300 mL) and water (300 mL). The organic layer was dried and thesolvent was removed ill vacuo. To the resulting oil was added diethylether (50 mL). and the resulting solid was collected and dried yieldingN-(2-Nitro-5-methylphenyl)-N′-phenyl-urea as a white solid.

EXAMPLE IV

A solution containing N-(2-Nitrophenyl)-N′-phenyl-urea (5.76 g) andchloroacetyl chloride (40 mL) was refluxed under nitrogen for 30 min.After the excess chloroacetyl chloride was removed in vacuo, diethylether (50 mL) was added and the resulting solid was filtered and driedto yield N′-(2-chloroacetyl)-N-(2-nitrophenyl)-N′-phenyl-urea as a whitesolid.

EXAMPLE V

A solution of N′-(2-Chloroacetyl)-N-(2-nitrophenyl)-N′-phenyl-urea (3.7g), dimethylformamide (15 mL) and diisopropylethylamine (15 mL) wasrefluxed for 5 min. The hot mixture was allowed to cool to roomtemperature and precipitated by adding the mixture to 200 mL of water.The precipitate was collected and dried to yield1-(2-Nitrophenyl)-3-phenyl-imidazoline-2,4(1H,3H)-dione.

EXAMPLE VI

To a solution of 1-(2-Nitrophenyl)-3-phenyl-imidazoline-2,4(1H,3H)-dione(2.7 g) in anhydrous dimethylformamide (2 mL) under nitrogen was addedN,N-dimethylformamide dimethyl acetal (2.7 g). The reaction was stirredat 80° C. for 2 h, and the solvent was removed in vacuo. To theresulting oil was added iron powder (5 g) and acetic acid (250 mL). Thismixture was carefully heated to reflux for 3 min followed by stirringthe reaction for an additional 30 min. The heterogeneous mixture wasdiluted with 10% methanol-methylene chloride (200 mL) and filteredthrough silica gel using 10% methanol/methylene chloride as eluant. Thesolvent was removed in vacuo and hot ethanol (200 mL) was added. To thismixture was added water (200 mL) and the resulting solid was filteredand washed successively with ethanol, ethyl acetate, diethyl ether anddried to yield 2-Phenyl-imidazo[1,5-a]quinoxaline-1,3(2H,5H)-dione as ayellow solid. (Compound 1) melting at 231-234° C.

EXAMPLE VII

To a solution containing1-(2-Nitrophenyl)-3-(2-fluorophenyl)-imidazoline-2,4(1H,3H)-dione (1.18g) in anhydrous methylene chloride (5 mL) under nitrogen was addedtris(dimethylamino)methane (1 mL). The reaction was stirred at roomtemperature for 20 min and the solvent was removed in vacuo. Theresulting solid was dissolved in dimethylformamide (100 mL) and a slurryof Raney nickel (50% solution in water, 1 mL) was added. The mixture washydrogenated at 50 psi for 45 min. After filtration through celite, thesolvent was concentrated in vacuo to 30 mL and water (50 mL) was added.The resulting solid was collected and washed successively with ethanol,ethyl acetate and diethyl ether and air dried to yield2-(2-Fluorophenyl)-imidazo[1,5,a]quinoxaline-1,3-(2H,5H)-dione as ayellow solid (Compound 2), m.p. 261-264° C.

EXAMPLE VIII

To a solution containing DMF (100 mL), H₂O (15 mL), 5% Pd-carbon (1.25g) and 1-(2-Nitrophenyl)-3-(4-ethoxyphenyl)-imidazoline-2,4(1H,3H)-dione(25 g) at 60° C. was added dropwise a solution containing sodiumhypophosphite (15 g) in H₂O (40 mL). After 3 hours the mixture wascooled to room temperature, and filtered through celite. The filtratewas poured into 500 mL of H₂O and filtered and dried to yield1-(2-Aminophenyl)-3-(4-ethoxyphenyl)-imidazoline-2,4(1H,3H)-dione.

EXAMPLE IX

To 1-(2-Aminophenyl)-3-(4-ethoxyphenyl)-imidazoline-2,4(1H,3 H)-dione (2g) was added DMF (5 mL), acetic acid (5 mL) and N,N-dimethylformamidedimethyl acetal (5 mL). The reaction mixture was heated to 60° C. for 16h, cooled and filtered. The resulting orange solid was washed withisopropanol and recrystallized from acetic acid to give2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione. m.p.268-269° C. (Compound 3).

The following compounds were prepared essentially according to theprocedures described in Examples VI, VII, and IX.

1. 2-(4-Methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 4). m.p. 240-242° C.

2. 2-(4-Methylphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound S). m.p. 305-308° C.

3. 2-(4-Fluorophenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 6). m.p. 235-238° C.

4. 2-(2- Aminophenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 7). m.p.247-249° C.

5. 2-(3.-Fluorophenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 8). m.p. 265-266° C.

6. 2-(4-Chlorophenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 9), m.p. 235-238° C.

7. 2-(3-Methylphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 10). m.p. 263-265° C.

8.2-(2-Fluoro-4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 11). m.p. 264-267° C.

9. 2-(3-Chlorophenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 12), m.p.235-239° C.

10. 2-(2-Methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 13). m.p.270-272° C.

11. 2-(4-Ethylphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 14). m.p. 215-216° C.

12.2-(2-Fluoro-4-methylphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 15). m.p. 280-284° C.

13. 2-(3-Methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 16). m.p. 212-214° C.

14. 2-(3-Ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 17). m.p. 197-200° C.

15. 2-(4-n-Propyloxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 18). m.p. 182-185° C.

16. 2-(4-n-Butoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 19), m.p. 155-156° C.

17. 2-(4-Isopropoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 20). m.p. 164-167° C.

18.7-Chloro-2-(4-methylphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 21). m.p. 200-204° C.

19.7,8-Dimethyl-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 22).

20. 8-Methyl-2-phenyl-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 23). m.p. 240-244° C.

21.8-Carboethoxy-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3-(2H,5H)-dione(Compound 24).

22.7-Carboethoxy-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3-(2H,5H)-dione(Compound 25).

23. 8-Bromo-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline1,3(2H,5H)-dione (Compound 26). m.p. 152-155° C.

24. 2-(4-Propylphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 27). m.p. 185-186° C.

25.7-Methyl-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 28). m.p. 200-203° C.

26.2-(3-Bromo-4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 29). m.p. 147-150° C.

27. 2-(3-Thienyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound30).

28. 2-(2-Thienyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound31).

29. 2-(4-Acetoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.(Compound 32). m.p. 210-211° C.

EXAMPLE XI

To a suspension of2-(4-Methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (100 mg)in anhydrous dioxane (4mL) was added bromine (200 mg). The reaction wasstirred at 20° C. for 15 min, and was then poured directly into boilingacetic acid (50 mL) containing zinc powder (500 mg). The reaction wasrefluxed for 5 min and allowed to cool to room temperature. Afterdilution with 10% methanol/methylene chloride (100 mL). the mixture wasfiltered through silica gel, the solvent was removed in vacuo, and theresulting solid was treated with boiling ethanol (25 mL) followed bydilution with water (100 mL). The mixture was cooled to 0° C. and thesolid was filtered and dried to yield8-Bromo-2-(4-methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 33) as a yellow solid. m.p. 154° (dec).

EXAMPLE XII

The following compound was made essentially according to the proceduredescribed in Example XI.

1.8-Bromo-2-(3-bromo-4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 34). m.p. 146-149° C.

EXAMPLE XIII

A solution containing 1-(2-Nitrophenyl)-3-(4-ethoxyphenyl)imidazoline-2,4(1H,3H)-dione (5 g) in anhydrous THF (50 mL) was addeddropwise over 30 min to a solution of 0.5 M LDA in THF (29 mL) at −78°C. After 20 min ethyl chloroformate (1.2 mL) in THF (5 mL) was added ina single portion. The reaction was warmed to room temperature over 30min and quenched with saturated ammonium chloride solution. The reactionmixture was partitioned between ethyl acetate and water, and the organiclayer was dried, and the solvent was removed in vacuo. Columnchromatography using silica gel with 50% ethyl acetate/hexane as theeluent yielded5-Carboethoxy-1-(2-nitrophenyl)-3-(4-ethoxyphenyl)-imidazoline-2,4(1H,3H)-dione.

EXAMPLE XIV

To a suspension containing zinc dust (6 g) in acetic acid (250 ml) wasadded5-Carboethoxy-1-(2-nitrophenyl)-3-(4-ethoxyphenyl)-imidazoline-2,4(1H,3H)-dione (2.5 g). The mixture was heated to reflux for 15 min,cooled to room temperature and filtered, the solvent was removed invacuo, and the resulting solid was stirred with ethanol (50 mL) andfiltered to yield4-Hydroxy-2-(4-ethoxyphenyl)-imidazo[1,5a]quinoxaline-1,3(2H,5H)-dione(Compound 35).

EXAMPLE XV

A solution of4-Hydroxy-2-(4-ethoxyphenyl)-imidazo[1,5,a]-quinoxaline-1,3(2H,5H)-dione(3.2 g) in phosphorous oxychloride (40 mL) was refluxed for 16 h. Thesolvent was removed in vacuo and water (15 mL) was added. The pH wasadjusted to 7.0 using ammonium hydroxide and this resulting solid wasfiltered and dried to yield4-Chloro-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 36).

EXAMPLE XVI

A solution of THF (10 mL), ammonia (10 mL) and4-Chloro-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(100 mg) was heated to 100IC in a sealed tube for 4 hours. After coolingto room temperature the solvent was removed in vacuo. The solid wasslurried in 50% EtOH—H₂O and filtered to yield4-Amino-2-(4-ethoxyphenyl-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 37).

EXAMPLE XVII

The following compounds were prepared essentially according to theprocedure described in example XVI:

1.4-Dimethylamino-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.(Compound 38).

2.4-n-Propylamino-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 39).

3.4-N-Methylamino-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 40).

EXAMPLE XVIII

2-(4-Acetoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (250 mg)was added to an ethanol solution (50 mL) saturated with HCl. Thesolution was stirred for 2 hours and the solvent was removed in vacuo toyield 2-(4-Hydroxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 41). m.p. 318-322° C.

EXAMPLE XIX

2-(4-Ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (100 mg)was added to a solution of dimethylformamide dimethylacetal (10 ml,) andDMF (5 mL), and the reaction mixture was heated to 100° C. for 4 h. Thesolution was cooled to room temperature and poured onto water (200 mL).The resulting precipitate was collected and dried to yield5-N-Methyl-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 42). m.p. 263-266° C.

EXAMPLE XX

2-(4-Ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione was addedto a solution of anhydrous DMF (5 mL) and potassium tert-butoxide (125mg) at 50° C. After 5 min trimethylacetyl chloride (150 mg) was added.The reaction was stirred for 15 min and then poured into water (25 mL).The resulting precipitate was collected, washed with EtOH and dried toyield3-Trimethylecetoxy-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 43).

EXAMPLE XXI

The following compounds were prepared essentially according to theprocedure described in Example XX:

1.3-n-Propyloxy-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1(2H,5H)-one(Compound 44).

2.5-Propionyl-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione(Compound 45).

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula I:

and the pharmaceutically acceptable non-toxic salts wherein: R₁ and R₄are the same or different and represent hydrogen, halogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; X is hydrogen,halogen, hydroxy, or amino; or mono- or dialkylamino where each alkyl islower alkyl having 1-6 carbon atoms; W is phenyl, thienyl, or pyridyl,or phenyl, thienyl, or pyridyl, each of which may be mono ordisubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, amino, mono of dialkylamino where eachalkyl is straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; R₂and R₃ are the same or different and represent hydrogen, halogen,hydroxy, amino, 1-indanyl, 4-(thio)chromanyl,1-(1,2,3,4-tetrahydronaphthyl); 1-indanyl, 4-(thio)chromanyl,1-(1,2,3,4-tetrahydronaphthyl), each of which is monosubstituted withhalogen, straight or branched chain lower alkyl having 1-6, carbonatoms, or straight or branched chain lower alkoxy having 1-6 carbonatoms: OR₅, COR₅, CO₂R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; —CONR₆R₇ or —(CH₂)_(n)NR₆R₇where n is 0, 1, or 2; R₆ is hydrogen, straight or branched chain loweralkyl having 1-6 carbon atoms; R₇ is hydrogen, phenyl, pyridyl, straightor branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl orpyridylalkyl where each alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms; or NR₆R₇ is a heterocyclic group which ismorpholyl, piperidyl, pyrrolidyl, or N-alkyl-piperazinyl; —NR₈CO₂R₉where R₈ and R₉ are the same or different and represent hydrogen,phenyl, pyridyl, straight or branched chain lower alkyl having 1-6carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms; orC(OH)R₁₀R₁₁ where R₁₁ and R₁₁ are the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms.
 2. A compound according to claim 1, whichis:

where: R₁ and R₄ are the same or different and represent hydrogen,halogen or straight or branched chain lower alkyl having 1-6 carbonatoms; X is hydrogen, halogen, hydroxy, or amino; or mono- ordialkylamino where each alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms; W is phenyl or a phenyl group mono ordisubstituted with halogen, hydroxy, amino, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.
 3. A compound according to claim 1,which is:

where: W is phenyl or a phenyl group mono or disubstituted with halogen,hydroxy, amino, straight or branched chain lower alkyl having 1-6 carbonatoms, or straight or branched chain lower alkoxy having 1-6 carbonatoms.
 4. A compound according to claim 1, which is:

where: W is phenyl or a phenyl group mono or disubstituted with halogen,hydroxy, amino, straight or branched chain lower alkyl having 1-6 carbonatoms, or straight or branched chain lower alkoxy having 1-6 carbonatoms; and R₂ ad R₃ are the same or different and represent hydrogen,halogen, hydroxy, amino, 1-indanyl, 4-(thio)chromanyl,1-(1,2,3,4-tetrahydronaphthyl); 1-indanyl, 4-(thio)chromanyl,1-(1,2,3,4-tetrahydronaphthyl), each of which is monosubstituted withhalogen, straight or branched chain lower alkyl having 1-6, carbonatoms, or straight or branched chain lower alkoxy having 1-6 carbonatoms; OR₅, COR₅, CO₂R₅, OCOR₅, or R₅, where R₅ is hydrogen, phenyl,pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms,or phenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carton atoms; —CONR₆R₇ or —(CH₂)_(n)NR₆R₇where n is 0, 1, or 2; R₆ is hydrogen, straight or branched chain loweralkyl having 1-6 carbon atoms; R₇ is hydrogen, phenyl, pyridyl, straightor branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl orpyridylalkyl where each alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms; or NR₆R₇ is a heterocyclic group which ismorpholyl, piperidyl, pyrrolidyl, or N-alkyl piperazinyl; —NR₈CO₂R₉where R₈ and R₉ are the same or different and represent hydrogen,phenyl, pyridyl, straight or branched chain lower alkyl having 1-6carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms; orC(OH)R₁₀ R₁₁ where R₁₀ and R₁₁ are the same or different and representstraight or branched chain lower alkyl having 1-6 carbon atoms, phenyl,or phenylalkyl where each alkyl is straight or branched chain loweralkyl having 1-6 carbon atoms.
 5. A compound according to claim 1,wherein W is phenyl.
 6. A compound according to claim 1, wherein R₂ isbromine.
 7. A compound according to claim 1, wherein W is4-methoxyphenyl.
 8. A compound according to claim 1, wherein W is2-fluorophenyl.
 9. A compound according to claim 1, wherein W is4-ethoxyphenyl.
 10. A compound according to claim 1, wherein W is2-thienyl.
 11. A compound according to claim 1, which is2-Phenyl-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 12. A compoundaccording to claim 1, which is2-(2-Fluorophenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 13. Acompound according to claim 1, which is2-(4-Ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 14. Acompound according to claim 1, which is2-(4-Methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 15. Acompound according to claim 1, which is2-(4-.Methylphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 16. Acompound according to claim 1, which is2-(4-Fluorophenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 17. Acompound according to claim 1, which is2-(2-Aminophenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 18. Acompound according to claim 1, which is2-(3-Fluorophenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 19. Acompound according to claim 1, which is2-(4-Chlorophenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 20. Acompound according to claim 1, which is2-(3-Methylphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 21. Acompound according to claim 1, which is2-(2-Fluoro-4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.22. A compound according to claim 1, which is2-(3-Chlorophenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 23. Acompound according to claim 1, which is2-(2-Methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 24. Acompound according to claim 1, which is2-(4-Ethylphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 25. Acompound according to claim 1, which is2-(2-Fluoro-4-methylphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.26. A compound according to claim 1, which is2-(3-Methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 27. Acompound according to claim 1, which is2-(3-Ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 28. Acompound according to claim 1, which is2-(4-n-Propyloxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione. 29.A compound according to claim 1, which is2-(4-n-Butoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 30. Acompound according to claim 1, which is2-(4-Isopropoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 31. Acompound according to claim 1, which is7-Chloro-2-(4-methylphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.32. A compound according to claim 1, which is7,8-Dimethyl-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline1,3(2H,5H)-dione.
 33. A compound according to claim 1, which is8-Methyl-2-phenyl-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 34. Acompound according to claim 1, which is8-Carboethoxy-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.35. A compound according to claim 1, which is7-Carboethoxy-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.36. A compound according to claim 1, which is 8-Bromo-2-(4ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 37. A compoundaccording to claim 1, which is2-(4-Propylphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 38. Acompound according to claim 1, which is7-Methyl-2-4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.39. A compound according to claim 1, which is2-(3-Bromo-4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.40. A compound according to claim 1, which is2-(3-Thienyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 41. A compoundaccording to claim 1, which is2-(2-Thienyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 42. A methodof treating overdoses of benzodiazepine drugs, which comprisesadministering an effective amount of a compound according to claim 1 toa patient in need thereof.
 43. A compound according to claim 1, which is8-Bromo-2-(4-methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.44. A compound according to claim 1, which is8-Bromo-2-(3-bromo-4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.45. A compound according to claim 1, which is4-Hydroxy-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 46. A compound according to claim 1, which is 4-Chloro-2-(4ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 47. A compoundaccording to claim 1, which is4-Amino-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.48. A compound according to claim 1, which is 4-Dimethylamino2-(4ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 49. A compoundaccording to claim 1, which is4-n-Propylamino-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.50. A compound according to claim 1, which is4-Methylamino-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.51. A compound according to claim 1, which is2-(4-Hydroxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione.
 52. Apharmaceutical composition comprising a compound according to claim 1,and at least one pharmaceutically acceptable carrier.
 53. A method oftreating anxiety, sleep, or seizure disorders, which comprisesadministering an effective amount of a compound according to claim 1 toa patient in need thereof.